The primary aim of these studies is to better understand the regulation and function of IGF-I during pregnancy. I postulate that IGF-I regulates changes in the growth and metabolism of maternal tissues that are necessary for a successful pregnancy, and that as pregnancy progresses, the relationships change among IGF-I, the IGF binding proteins (IGFBPs) which modify IGF action, and the Type I IGF receptor (IGFI-R). To determine the changes in tissue-specific expression of IGF-I, IGFBPs and the IGF-I receptor during pregnancy, steady-state mRNA levels of IGF-I, IGFBPs (IGFBP-l, IGFBP-2 and IGFBP-3) and IGFI-R will be measured by solution and/or Northern hybridization in maternal liver, kidney, heart, skeletal muscle, uterus and placenta at 9, 12, 15, 18 and 2l days of pregnancy. These mRNAs will be localized to specific cell types using in situ hybridization. Tissue concentrations of IGF-I, the abundance of IGFI-Rs in cell membranes and of IGFBPs in cell cytosol will be determined to learn whether changes in mRNA abundance correlate with changes in peptide abundance. IGF-I circulates in serum in association with specific high-affinity binding proteins (IGFBPs) in high and low MW complexes that presumably modulate the uptake and endocrine action of IGF-I in tissues. To determine the consequences of changes in serum IGFBP concentrations, the IGFBP composition of the high and low MW complexes and the in vivo clearance and tissue uptake of [125I)IGF-I during early, mid-, and late pregnancy will be determined. Protease activity that degrades IGFBP-3 is induced between days 12 and 15 of rat pregnancy, corresponding with dramatic decreases in ICFBP-3 and IGF-I serum concentrations. Although a long range goal is to purify this protease, the protease will first be characterized by determining its mechanism of action, its site(s) of production, the range of its expression, species-specificity among mammals, changes in its expression during pregnancy, and its effect on IGF-I uptake and metabolism in vivo. Finally, the mechanisms by which changes in dietary protein alter ICF-I, IGFBP and IGFI-R expression during pregnancy will be determined and correlated with alterations in maternal and placental growth. In addition to extending our knowledge of IGFs in pregnancy, these studies should provide new insights into the role of IGFBPs in modulating autocrine, paracrine, and endocrine actions of IGF-I.